Elucidating genetic aberrations in pediatric acute myeloid leukemia (AML) provides insight in biology and may impact on risk-group stratification and clinical outcome. This study aimed to detect such aberrations in a selected series of samples without known (cyto)genetic aberration using molecular profiling. A cohort of 161 patients was selected from various study groups: DCOG, BFM, SJCRH, NOPHO and AEIOP. Samples were analyzed using RNA sequencing (n=152), whole exome (n=135) and/or whole genome sequencing (n=100). In 70 of 156 patients (45%), of whom RNA sequencing or whole genome sequencing was available, rearrangements were detected, 22 of which were novel; five involving ERG rearrangements and four NPM1 rearrangements. ERG rearrangements showed self-renewal capacity in vitro, and a distinct gene expression pattern. Gene set enrichment analysis of this cluster showed upregulation of gene sets derived from Ewing sarcoma, which was confirmed comparing gene expression profiles of AML and Ewing sarcoma. Furthermore, NPM1-rearranged cases showed cytoplasmic NPM1 localization and revealed HOXA/B gene overexpression, as described for NPM1 mutated cases. Single-gene mutations as identified in adult AML were rare. Patients had a median of 24 coding mutations (range, 7-159). Novel recurrent mutations were detected in UBTF (n=10), a regulator of RNA transcription. In 75% of patients an aberration with a prognostic impact could be detected. Therefore, we suggest these techniques need to become standard of care in diagnostics.

AML BFM Study Group Pediatric Hematology and Oncology Essen

Center of molecular biology and gene therapy Department of Internal Hematology and Oncology Masaryk University Hospital Brno Czech Republic

Department of Cell Biology Erasmus MC Rotterdam

Department of Oncology St Jude Children's Research Hospital Memphis Tennessee

Department of Pathology St Jude Children's Research Hospital Memphis Tennessee

Department of Pediatric Hematology and Oncology Aghia Sophia Children's Hospital Athens

Italian Association of Pediatric Hematology and Oncology University of Pavia Pavia

Nordic Society for Pediatric Hematology and Oncology Department of Pediatrics Institution for Clinical Sciences Sahlgrenska Academy University of Gothenburg Gothenburg

Pediatric Oncology Hematology Erasmus MC Sophia Children's Hospital Rotterdam

Pediatric Oncology Hematology Erasmus MC Sophia Children's Hospital Rotterdam The Netherlands; Princess Máxima Center for Pediatric Oncology Utrecht

Pediatrics and Adolescent Medicine Aarhus University Hospital Aarhus

US Biologic Inc Memphis Tennessee

Women and Child Health Department Hematology Oncology Clinic and Lab University of Padova Padova

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